The remodelling of bone depends on a balance between bone formation and bone resorption. Osteoblasts are responsible for the formation of new bone osteoid, composed mainly of nonmineralized type 1 collagen. Bone resorption is mediated by large multinucleated cells called osteoclasts. To resorb bone, osteoclasts first establish zones of dose contact with the mineralized matrix. This forms a protected compartment between the osteoclast and the bone matrix interface in which an acidic microenvironment is formed. Within these zones bone is demineralized, and the collagen fibres resorbed by the action of secreted lysosomal hydrolases. A number of factors have been shown to be potent stimulators of bone resorption both in vitro and in vivo. These include parathyroid hormone, 1,25-dihydroxyvitamin D3 prostaglandin-E2 or -I2, IL-1, TNF-α, TNF-βand bone-derived growth factors. None of these factors directly affect osteoclastic function; all require the presence of osteoblasts.
Increased bone resorption is a hallmark of a variety of clinical conditions. In some common bone disorders, the balance between the process of resorption and formation remains normal, but the rate of bone turnover is much higher. Most cases of primary hyperparathyroidism. Paget's disease, and thyroxicosis are in this category. In other common diseases, there is an imbalance between resorption and formation. Whether increased resorption or impaired formation predominates, however, the consequence is the same, i.e., diminished total bone mass. Thus, improper maintenance of bone occurs not only in postmenopausal women but is also a frequent complication of metastatic bone cancer, myeloma, and Paget's disease of bone. The present invention specifically comtemplates that subject methods can be used as part of a treatment protocol for disorders marked by imbalance between resorption and formation and/or increased bone resorption.
Interleukin-11 (IL-11) has a role, either alone or in combination with other cytokines, in bone formation/resorption.
IL-11 belongs to a family of cytokines which includes interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and oncostatin M(OSM). These cytokines have similar tertiary structures, share a common signal transducer (gp130) and have overlapping biological activities. In order for these cytokines to elicit a biological response, a tertiary complex, comprising the cytokine, its specific receptor (alpha chain), and gp130 must be formed.